1. Field of Invention
This invention relates to self-tumor antigens and methods and compositions to generate immunity in humans against self tumor antigens. This invention is more particularly related to eliciting or enhancing immunity against human self tumor antigen encoded by unconventional reading frames with homology to foreign proteins
2. Description of Related Art
Self-tumor antigens that elicit anti-tumor immune responses in responses to interferon-α (IFN-α) stimulation remain poorly defined. Currently, most of tumor antigens and autoantigens are encoded by primary open reading frames in mRNAs.
A new generation of tumor antigens has been defined as “self proteins” (J. Exp. Med. 180:1-4, 1994; Cell 82:13-17, 1995). Self tumor antigens are proteins that are expressed by both normal cells and cancer cells. (As opposed to mutated proteins that are unique and thus cancer specific.) Self tumor antigens are typically overexpressed by the cancer cells. Certain self proteins, such as HER-2/neu and c-myc, are known to be involved in malignant transformation. See U.S. Patent Publication No. 2002/0019331 to Cheever.
Internal ribosome entry site associated studies have been extensive in biochemistry field but not immunology fields, e.g., tumor immunology field. The practical use of internal ribosome entry site is limited in construction of bicistronic vectors for gene therapy and construction of bicistronic vectors for gene expression.
Due to the difficulties in the current approaches to treatment and prevention of cancer, there is a need in the art for improved methods and compositions. The present invention fulfills this need, and further provides other related advantages.
The invention provides several new self-tumor antigens, MPD5, PV65 (eIF-2α) and PV13 (protamine 2), which have been found to be immunogenic in patients with polycythemia vera, a myeloproliferative disease. These conventional self-tumor antigens can be used for diagnosis and prognosis, as well as the target for future immunotherapy.
The inventor screened a human testis cDNA library with sera from three polycythemia vera (PV) patients who responded to IFN-α and identified novel antigens, MPD5, PV13 (protamine 2) and PV65 (eIF-2α). These antigens elicit IgG antibody responses in a subset of PV patients but not in healthy donors, suggesting that they are authentic tumor antigens, suggesting that they are immunogenic tumor antigens. Increased phosphorylation of PV65 in response to stimulation of IFN-α, and upregulation of PV13 in tumor cells might enhance their abilities in elicitation of immune reactions in patients. These findings provide new insights into the mechanism underlying the regulation of the self-antigen repertoire in eliciting anti-tumor immune reactions in patients with polycythemia vera, and suggest their potential as the targets of novel immunotherapy. This invention is the first demonstration that phosphorylation of tumor antigen increases the immunogenicity of tumor antigens, suggesting posttranslational modifications of proteins, such as phosphorylation, can be targeted for diagnosis and immunotherapy. These antigens can elicit anti-tumor IgG antibody responses, and T cell responses. Since these two tumor antigens are non-mutated antigens, therefore, this antigen can be used for diagnosis, prognosis and immunotherapy for viral infections, inflammation, autoimmune diseases and tumors. The inventor has discovered that polycythemia vera is a myeloproliferative disease. This invention is the first report showing that anti-tumor immune responses, elicited by these self-tumor antigens, MPD5, PV13 (protamine 2) and PV65 (eIF-2α), leads to tumor remission. The inventor has found that immune responses to MPD5, PV13 and PV65 self-tumor antigens can be targeted for the purposes of diagnosis, prognosis and immunotherapy for viral infections, inflammation, autoimmune diseases and tumors. The inventor has further found that interferon-α stimulation enhances anti-tumor immune responses via promotion of posttranslational modifications of protein antigens.
All references cited herein are incorporated herein by reference in their entireties.